Intramuscular glutamine is decreased by as much as 70-80% in patients with severe burns or sepsis. The applicant has shown that glutamine intake alone cannot restore the normal intracellular concentration in these patients. The primary goal is to determine the mechanism responsible for this decrease. The investigators will test three general hypotheses relevant to the goal. (1) Muscle glutamine production is limited because of a deficiency in its precursor, glutamate and that this deficiency is due to the rapid transamination of glutamate with pyruvate to form alanine; (2) transmembrane transport of glutamine is altered in burns or sepsis to favor outward efflux; (3) intracellular glutamine concentration plays a roll in regulating muscle protein synthesis and breakdown. These hypotheses will be tested using the leg model that combines artero-venous sampling and tissue biopsies with stable isotope tracer methodology to quantify muscle amino acid and protein kinetics and transmembrane transport. Hypothesis 1 will be tested by decreasing the availability of pyruvate by infusion of dichloroacetate or by increasing the availability of alpha-ketoglutarate, a precursor of glutamate. Hypothesis 2 will be tested by comparison of the rate of glutamine transport in burned or septic patients with that of normal volunteers in both the post- absorptive state and at the end of a 24-hour continuous intravenous infusion of glutamine. Hypothesis 3 will be tested by quantifying muscle protein synthesis and breakdown before and after intramuscular glutamine concentration is increased by the combined infusion of dichloroacetate, alpha-ketoglutarate, and glutamine. These studies should provide novel basic information about the normal regulation of glutamine levels and protein metabolism. They may also generate an effective therapeutic approach to help prevent muscle wastage in these patients.
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